Colon cancer is the second leading cause of cancer deaths in the United States. Chronic inflammation contributes significantly to the etiology of colon cancer development. We propose that certain forms of vitamin E are excellent anti-cancer agents for colon cancer. Vitamin E comprises eight molecules, 1-, 2-, 3-, 4-tocopherol and 1-, 2-, 3-, 4-tocotrienol. Among them, only 1-tocopherol (1T), the predominant form of vitamin E in tissues, has been extensively studied including its chemoprevention potential for colon cancer, but the results are disappointing. Recent studies by us and others indicate that 3-tocopherol (3T), which is rich in US diets, may be a much better anticancer agent than 1T. In particular, we have shown that 3T but not 1T has anti-inflammatory properties by inhibition of cyclooxygenase (COX)-catalyzed prostaglandin E2 in cultured cells and in a rat inflammation model. Our preliminary data showed that 3T more potently inhibits 5-lipoxygnease (5-LOX)-catalyzed formation of leukotriene B4 than 1T. A new metabolite of 3T, 13'-carboxychormanol, which is detected in significant amounts in feces, is an even stronger inhibitor of COXs and 5-LOX than 3T. In addition to the anti-inflammatory properties, our preliminary data indicated that 3T may inhibit growth and induce apoptosis in colon cancer cell lines by modulation of sphingolipid synthesis. Recently, a study reported that mixed tocopherols, which are enriched in 3T, inhibited aberrant crypt foci formation in azoxymethane-induced colon cancer model. This intriguing finding together with our observations leads to the current hypothesis that 3T is effective in prevention against colon cancer via mechanisms including anti-inflammatory action and potential modulation of sphingolipids. This hypothesis will be tested by pursuit of the following Specific Aims: 1) Investigate anti-angiogenic effect of 3T and 1T via the anti-inflammatory mechanism;2) investigate potential modulation of sphingolipids and its relevance to 3T-mediated antiproliferation and pro-apoptosis effect in colon cancer cell lines;and 3) Examine anti-cancer effects of 3T and 1T in a colitis-associated colon cancer model, and investigate the mechanisms underlying the observed effects. These studies will elucidate new anti-cancer mechanisms of 3T, potentially identify a new drug target for colon cancer and provide important preclinical data for future human clinical studies. PUBLIC HEALTH RELEVANCE: The proposed study will provide strong evidence that gamma-tocopherol, the major form of vitamin E in US diet, is an effective chemoprevention and therapeutic agent for colon cancer. These studies will also provide biochemical mechanisms and important preclinical data for future human clinical studies.